This project defines how mechanisms of aging, biological changes with age, and life spans are affected by specific deficiencies in the insulin and IGF-1 pathways in mice. The broad objectives are to understand effects of the insulin/IGF-1 pathways on mammalian aging, and to retard deleterious changes with age in human beings. The following hypotheses are tested: Aim 1: That, in mice, elimination of insulin signaling in specific tissues reproduces the benefits of (a) the combined insulin/IGF-1 signal impairment of the Ghrhrlit (lit/lit) mutation or of (b) diet restriction (DR); also, that the effects of the (lit/lit) mutation reproduce effects of DR. Changes with age in mice targeted to lack the insulin receptor (IR) in white fat (FIRKO), in neural tissue (NIRKO), and in both (FIRKO & NIRKO) are contrasted with aging in the lit/lit mutant, and in the DR-treated mouse. Here and in Aims 2 & 3, the C57BL/6J X C3H/HeJ F1 hybrid (B6C3HF1) background provides a robust standardized foundation for direct comparisons. Aim 2: That the beneficial effects of reduced insulin and IGF-1 signaling are additive. The effects of the combined mutants ([FIRKO & lit/lit\, [NIRKO & lit/lit], and [FIRKO & NIRKO & lit/lit) are compared with the mutants in Aim 1 and with DR, to determine whether the benefits of the impaired insulin pathway in specific tissues are redundant, additive, or synergistic to the diminished insulin and IGF-1 of lit/lit mutants. Aim 3: That reduction in insulin signaling, not adiposity, mediates beneficial effects on aging in FIRKO mice. The hyperphagic Lepob (ob/ob) mutation is combined with the FIRKO mutation, producing obese FIRKO mice, to test if aging rates are retarded despite increased levels of body fat. Health relevance: In each aim, aging mechanisms and rates are tested in biological systems with clinical relevance: resistance to leukemias or oxidation; rates of aging in collagen, T cells, body composition, metabolism, glucose, insulin, IGF-1, leptin, hematocrit and bone composition; life spans and pathological lesions. These experiments define function of the insulin and IGF-1 pathways as regulators of underlying mechanisms causing increases, with age, in vulnerability to disease and death. Understanding how reductions in function of the insulin and IGF-1 pathways delay aspects of mammalian aging may suggest treatments to improve health as human beings age. [unreadable] [unreadable] [unreadable]